Accurate, noninvasive assessment of myocardial perfusion is the cornerstone for diagnosis of coronary artery disease and for the objective evaluation of the efficacy of interventions designed to augment nutritive perfusion. Positron emission tomography (PET) is an intrinsically quantitative imaging technique which permits the three- dimensional reconstruction of the distribution of positron-emitting tracers within the body. We and others have previously demonstrated that myocardial perfusion can be delineated in absolute terms (i.e., ml/g/min) over a wide range of flows and pathophysiological conditions in both experimental animals and in human subjects using the cyclotron produced flow tracers oxygen-15 labeled water and nitrogen-13 labeled ammonia. Based on the usefulness of these approaches, a number of cardiac PET centers are being established for the clinical evaluation of patients. However, many of these centers do not have access to cyclotron-produced radiotracers and therefore use the generatorproduced extractable perfusion tracers rubidium-82 chloride and copper-62-pyruvaldehyde bis-N4-methylthiosemicarbazone (PTSM) for estimates of flow. Although qualitative interpretation of count-based images does provide diagnostic capabilities, to fulfill the potential of PET for quantification of perfusion in absolute terms, the biological behavior of each tracer must be defined using physiologically appropriate mathematical models. Accordingly, the aim of the proposed research is to modify and implement mathematical models which best describe the biological behavior of rubidium-82 chloride and copper-62 PTSM and to evaluate their utility and limitations in quantifying myocardial perfusion over wide range of flows. During the first year of the proposed research models will be implemented and evaluated using computer simulations and error analysis. In year two, the mathematical approaches will be prospectively compared in intact dogs studied over a wide range of flows and physiological conditions including ischemia, reperfusion, and coronary hyperemia with flow estimated by concomitantly administered radiolabeled microspheres. In the third and fourth years of the proposed project, the most promising approaches will be evaluated in human subjects. The results of this research will enable centers that use generator-produced positron emitting flow tracers to implement mathematical models for quantitative estimates of myocardial perfusion and thereby improve the diagnostic accuracy of such techniques in the evaluation of patients with cardiac disease.